The emerging technology of nanoparticle packaging offers a way to package and deliver compounds of interest that offers significant advantages, in some cases, to delivering certain types of payloads, such as pharmaceuticals, antibodies, and labeling compounds. Many pharmaceutical agents are vulnerable to a reduction in efficacy due to solubility and bioavailability problems. Nanoparticle packaging offers a way to improve their effectiveness. By the appropriate design of nanoparticles, the serum stability of pharmaceutical agents can be enhanced and solubility limitations bypassed.
Nanoparticles also offer the potential, at least, for targeted delivery of their payloads to areas of specific interest. Frequently, an affinity reagent, such as an antibody attached externally to the nanoparticle, is used to direct the nanoparticle to its intended location. A wide variety of nanoparticles are currently available and/or under development. One particular type of nanoparticle is the dendrimer (see, e.g., Cheng, Y., J. Wang, T. Rao, X. He, T. Xu, T.; “Pharmaceutical applications of dendrimers: promising nanocarriers for drug delivery”; Front. Biosci. 13 (2008) 1447-1471.)
Commercially available dendrimers include polyamidoamine (“PAMAM”) dendrimers and polypropylene imine (“PPI”) dendrimers. Some representative examples of dendrimers and their uses are disclosed in U.S. Pat. Nos. 6,579,906, 6,570,031, 6,545,101, 6,506,218, 6,464,971, 6,452,053, 6,410,680, 6,395,257, 6,365,562, 6,306,991, 6,288,253, 6,228,978, 6,224,898, 6,187,897, 6,184,313, 6,113,946, 6,083,708, 6,068,835, 5,990,089, 5,938,934, 5,902,863, 5,788,989, 5,736,346, 5,714,166, 5,661,025, 5,648,186, 5,393,797, 5,393,795, 5,332,640, 5,266,106, 5,256,516, 5,256,193, 5,098,475, 4,938,885 and 4,694,064.
Forming dendrimers into nanoparticles and/or microparticles, however, does not fully address the question of bioavailability of substances carried by the dendrimers. With the rapid progress of nanotechnology over the past decade, there is growing interest in polymeric biomaterials that can be remotely disassembled in a controlled fashion with an external stimulus, but are otherwise stable under physiological conditions (Wang, W.; Alexander, C. Angew. Chem. Int. Ed., 2008, 47, 7804-7806). Various internal and external stimuli, such as pH, specific enzymes, temperature, and ultrasound are being explored as release mechanisms. (See, e.g., Murthy, N. X., M.; Schuck, S.; Kunisawa, J.; Shastri, N.; Frechet, J. M. J. Proc. Natl. Acad. Sci. U.S.A., 2003, 100, 4995-5000; Veronese, F. M. S., O.; Pasut, G.; Mendichi, R.; Andersson, L.; Tsirk, A.; Ford, J.; Wu, G.; Kneller, S.; Davies, J.; Duncan, R., Bioconjugate Chem., 2005, 16, 775-784; Chung, J. E. Y., M.; Yamato, M.; Aoyagi, T.; Sakurai, Y.; Okano, T. J. J., Controlled Release, 1999, 62, 115-127; Liu, S. Q.; Tong, Y. W.; Yang, Y. Y., Biomaterials, 2005, 26, 5064-5074; Na, K.; Lee, K. H.; Lee, D. H.; Bae, Y. H., Eur. J. Pharm. Sci., 2006, 27, 115-122; Gao, Z. G.; Fain, H. D.; Rapoport, N. J., Controlled Release, 2005, 102, 203-222; Nelson, J. L.; Roeder, B. L.; Carmen, J. C.; Roloff, F.; and Pitt, W. G. Cancer Research 2002, 62, 7280-7283).
One of these promising approaches is the use of light to trigger the remote disassembly of polymers (Goodwin, A. P.; Mynar, J. L.; Ma, Y. Z.; Fleming, G. R.; Frechet, J. M. J. J. Am. Chem. Soc. 2005, 127, 9952-9953). Light stimulus is especially attractive as it can be remotely applied for a short period of time with high spatial and temporal precision. Some forms of light, such as near-infrared (NIR) light, can penetrate deep into tissue and thus potentially have many in vivo applications (see, e.g., Near-Infrared Applications in Biolechnology; Raghavachari, R., Ed.; Practical Spectroscopy Series 25; Marcel Dekker: New York. 2001).
Two-photon excitation microscopy, for example, has been used as an alternative to confocal and deconvolution microscopy that provides distinct advantages for three-dimensional imaging. In particular, two-photon excitation excels at imaging of living cells, especially within intact tissues such as brain slices, embryos, intact organs, and even entire animals. Two-photon excitation microscopy provides superior optical sectioning at greater depths in thick specimens than is possible by other methods. This ability to see within tissues demonstrates the practicality of using two-photon technology for other purposes within a tissue and/or organism.
Three-photon excitation is a related non-linear optical absorption event that can occur in a manner similar to two-photon excitation. The difference is that three photons must interact simultaneously with the fluorophore to illicit a transition to the excited singlet state. A benefit of three-photon excitation is that successful absorption requires only a tenfold greater concentration of photons than two-photon absorption, making this technique attractive for some experiments.
Multi-photon phenomena allow unparalleled spatio-temporal control, and where longer wavelengths are employed, also allow deeper penetration into turbid bulk media such as tissue. Despite the revolutionary impact these phenomena have had on neuroscience, microscopy and lithography, it has been generally very difficult to apply this technique in vivo to stimulate and/or deliver biomaterials, diagnostics, and/or drugs. The technology for fully exploiting these advantages has lagged behind and there is still an unmet need for biomaterials that can efficiently respond to light, especially NIR light. No robust systems currently exist for in vivo use of multi-photon-responsive materials to deliver Payloads of interest.